Management of malignant pleural mesothelioma
Pervin Hürmüz, Trabzon Numune Eğitim ve Araştırma Hastanesi, Radyasyon Onkolojisi Bölümü, Maraş Caddesi, İnönü Mahallesi, Trabzon, TURKEY.
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Malignant pleural mesothelioma is a rare neoplasm arising from the surface serosal cells of the pleural cavity. More than 80% of cases of malignant pleural mesothelioma have been attributed to asbestos exposure. In its natural course median survival is 4 to 12 months. If untreated most of patients die due to local complications of the disease. Surgery improves local control but is not sufficient as a single treatment modality. The recommended treatment strategy for a select group of patients is multimodal therapy that includes surgery, radiotherapy and chemotherapy.
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from the surface serosal cells of the pleural cavity. The first report of a primary pleural tumor is attributed to Lieutaud in 1767, but the first accurate pathological description was reported in 1937.1 Predominantly this tumor affects men over 50 years of age (male to female ratio 3:1). It is a unilateral disease in 95% of cases that is commonly seen on the right side of the thoracic cavity (60%).2
The estimated annual incidence of mesothelioma in the United States is estimated to be 2200 cases per year, showing an increase over the last decade.3,4 Due to the long latency period (at least 20 years) between asbestos exposure and the development of the disease, an increase in the incidence of MPM is expected in the coming years. By 2020 in Great Britain 2700–3000 deaths per year are expected from mesothelioma.5 However these numbers are anticipated to decrease in developed countries due to legislation which has reduced asbestos exposure in the workplace and general environment. The rates are predicted to increase in undeveloped countries due to the poor regulation of asbestos mining and the increase in industrial and household use of asbestos.6
Epidemiological studies have established that exposure to asbestos fibers is the main cause of mesothelioma. Simian virus 40 (SV40) and genetic predisposition also play a role in the etiology of the disease.7–9
Asbestos is the name of a group of hydrated magnesium silicate fibrous minerals that is divided into two groups: amphibole and serpentine. The amphibole fibers, especially crocidolite asbestos, are most clearly associated with MPM, whereas chrysotile, a serpentine fiber, has shown to be less carcinogenic.4,5,10
Asbestos is resistant to heat and combustion so it has been used in the production of cement, ceiling tiles, automobile brake linings and shipbuilding. Asbestos workers are at high risk for the development of pulmonary disease. The risk of development of mesothelioma among asbestos workers is thought to be 8–13%.6
Simian virus 40
SV40 is a DNA virus that binds and inactivates critical tumor suppression gene products such as p53 and pRB and stimulates met, Notch-1 and telomerase activity. It was transferred to many people through virus contaminated polio vaccines between 1954 and 1963. The presence of SV40 sequences in 60% of human mesothelioma tissue samples supports the association of the virus with the disease. However, the virus was not detected in Finnish, Austrian and Turkish mesothelioma tissue specimens. This may be related to the fact that the contaminated vaccines were not administered in those countries.9–13
In certain villages of Central Anatolia, Turkey, it was found that more than 50% of the mortality rate was due to mesothelioma. Epidemiological studies in this region revealed that houses contain a non-asbestos fiber called erionite. This fiber is present in the volcanic tuff used in the construction of houses and also found in the air of the villages.14,15 Intrapleural injection of erionite to animals caused mesothelioma in in vitro studies,16 thus it was concluded that erionite was the cause of mesothelioma in these villages.15–18 The people living in these villages share the same house for a lifetime with many generations. Although all the houses in this region contain a similar amount of erionite, mesotheliomas occurred only in the members of certain families living in the same homes. The analysis of pedigrees of these families showed that the disease is inherited in an autosomal dominant pattern.8,19 It is unknown whether genetics alone or together with erionite is responsible for the disease, but the occurrence of mesothelioma only in the affected families supports the importance of genetics in the etiology.10
MPM is classified into three histological subtypes: epithelial, sarcomatoid and biphasic (combination of both). Epithelial mesotheliomas are the most common types (50–60% of cases) and have a better prognosis than the other two forms. Sarcomatoid mesotheliomas, comprising 10% of cases, are quite resistant to therapy and have a median survival rate of less than a year.3,10
Electron microscopy is the golden standard in the diagnosis of mesothelioma. Immunohistochemistry is valuable in the differentiation of epithelial mesothelioma from pulmonary or metastatic adenocarcinoma, but still there is no single antibody to make this decision alone. Although antibodies against cytokeratin proteins are strongly positive in mesothelioma, this is not enough to differentiate it from adenocarcinoma. The carcinoembryonic antigen (CEA) and Leu-M1, which are typically positive in adenocarcinoma, are negative in mesothelioma. There are positive and negative markers used for distinguishing mesothelioma from other tumors. It is recommended to use four markers (two negative and two positive). Calretinin, cytokeratin 5/6 and WT1 are the positive markers. Negative markers for mesothelioma are CEA, MOC-31, Ber-EP4, BG-8 and B-72-3.4,20
The most common symptoms of MPM are dyspnea and chest pain. In some asymptomatic patients unilateral pleural effusion might be found on chest X-ray. Physical examination shows signs of pleural effusion, such as decreased breath sounds and dullness to percussion.
The laboratory examinations for mesothelioma are non-specific, however, it was shown that 14% of patients have elevated homocysteine levels, while 17% of patients have vitamin B12 deficiency and 32% of patients have folic acid deficiency.21 Thrombocytosis is seen in 60–90% of patients.22 There are no serum tumor markers specific to the disease. Screening for mesothelin might have a potential benefit.23 Soluble mesothelin has good specificity but has low sensitivity, being negative in all sarcomatoid mesothelioma and in up to one half of epithelioid mesothelioma. Mesothelin is also a capable marker for monitoring response to treatment, but it is still early to make recommendations. Further studies are needed.24,25,26
Chest X-ray shows unilateral pleural fluid, diffuse pleural thickening and nodularity. Thorax computed tomography (CT) is important in the evaluation of chest wall, ribs and mediastinal structures. However, magnetic resonance imaging (MRI) is superior to CT for detection of diaphragmatic, endothoracic fascia or chest wall invasion.27,28 Positron emission tomography (PET) scanning with 18-fluorodeoxyglucose (FDG) is effective for finding extrathoracic disease, however it has limited sensitivity for local/regional staging.29,30 The standard uptake value (SUV) is important in estimating the prognosis of patients. High-SUV tumors are associated with a 3.3 times greater risk of death than low-SUV patients. SUV of >4 and mixed histology are poor risk factors for MPM.31 Gerbaudo et al. showed that the pattern, intensity and kinetics of 18-FDG uptake in mesothelioma are good indicators of tumor aggressiveness.32 Integrated PET/CT increases the accuracy of staging and response to treatment.27,33 It was shown that PET/CT is able to stage patients with limited MPM with high accuracy and low interobserver variability,34 therefore improving the selection of patients for curative surgical resection.35 Wilcox et al. showed that PET/CT findings excluded 14 out of 35 patients from surgical intervention. However, it was concluded that the ability of this imaging modality to correctly stage locoregional disease is not superior to the combination of CT and MRI.36
Pleural effusions are initially investigated by thoracentesis but in most cases mesothelioma and other types of cancer that are related with pleural effusions require biopsies for definite diagnosis. Nonetheless, the disease can be diagnosed by thoracentesis in 26% of cases and by closed pleural biopsy in 39% of cases.6 Thoracoscopy (video assisted thoracic surgery (VATS)) is performed when patients have pleural effusion but the previous pleural biopsy or thoracentesis was negatively reported. VATS produces large, visually guided biopsy samples and is diagnostic in 98% of cases.9 Open pleural biopsy is required when the pleural space is solid.
Median survival for MPM patients is 4–12 months. After the use of intensive combined treatments and new generation antifolate agents a 3–4 month survival advantage was reported.37,38 Patients can have dyspnea and pneumonia due to the tumor mass, cachexia due to dysphagia, myocardial dysfunction resulting in arrhythmia and chest pain requiring narcotics. If untreated most patients die due to local complications of the disease.
Thrombocytosis, leukocytosis, low hemoglobin, fever of unknown origin, sarcomatoid or mixed histology, age ≥65, poor Eastern Cooperative Oncology Group (ECOG) performance status, and male sex are all associated with poor prognosis. Epithelial histology, stage I disease, age <65, ECOG performance status 0–1, absence of chest pain and presence of symptoms for more than six months prior to diagnosis are good prognostic factors.10,39
There are two important prognostic indexes, one derived by the Cancer and Leukemia Group B CALGB and the European Organization for Research and Treatment of Cancer (EORTC). According to the CALGB prognostic index, serum lactate dehydrogenase level >500 IU/L, poor ECOG performance status, chest pain, platelet count > 400000/µL, non-epithelial histology and age >75 are associated with poor survival.40 According to the EORTC prognostic index, poor performance status, leukocytosis, male sex, and sarcomatoid type histology are poor prognostic factors.41
The American Joint Commission on Cancer staging system for mesothelioma is based on the International Mesothelioma Interest group staging system.42
Median survival of the patients who select supportive care ranges from 4 to 12 months.43,44 For the control of pleural effusion thoracentesis, talc pleurodesis, pleuroperitoneal shunting and placement of catheter can be performed. The chest pain of patients that affects quality of life should be managed. These patients should be evaluated by pain a management team. If local radiotherapy has been delivered for chest wall pain or nodules, the median survival has been reported to be 4 to 5 months.45,46 A multicenter randomized trial showed that addition of chemotherapy (CHT) to active symptom control offers no significant benefits in terms of overall survival or quality of life. However, it was concluded that addition of vinorelbine deserves further investigation.47
Surgery for MPM can be diagnostic, palliative or curative. The decision is made according to the extent of the disease, the performance of the patient and the experience of the treating institution.
Pleurodesis is effective in the treatment of dyspnea which is due to pleural effusion. Pleural effusion is drained by tube thoracostomy or video thoracoscopy and a sclerosing agent is inserted into the pleural space. The most commonly used sclerosing agent is sterile, asbestos-free talc that was shown to induce apoptosis in mesothelioma cell lines in vitro.48 If the pleural space is filled with tumor or the lung is trapped by thick visceral pleural tumor, pleurodesis is ineffective. In this case the palliation of dyspnea is achieved by pleuroperitoneal shunt or semi-permanent pleural catheters.49,50 The risk of the implantations of these procedures should not be forgotten.
Pleurectomy and decortication (P/D) are more effective than talc pleurodesis in controlling malignant pleural effusion.51,52 The purpose of this procedure is to remove the gross tumor without removing the lung. It is generally performed on patients with locally contained mesothelioma with little advancement into adjacent tissue. For patients who are diagnosed with limited tumor burden, P/D is likely to be a good option to achieve complete resection. The most common complications are prolonged air leak (10% of patients), pneumonia, respiratory insufficiency, emphysema (2%), and hemorrhage (<1%). The mortality rate is 1% and death is either due to respiratory insufficiency or hemorrhage.53,54
Extrapleural pneumonectomy (EPP) is an en bloc resection of the pleura, the lung, ipsilateral hemidiaphragm, and pericardium. Reconstruction of the diaphragm and pericardium (if it has been resected) is performed. This prevents the herniation of abdominal organs and the heart into the empty hemithorax. EPP provides the greatest cytoreduction and allows higher radiation doses to be delivered to the ipsilateral hemithorax as the lung has been removed. EPP is the standard surgery in many multimodal treatment protocols as it allows macroscopic negative resection margins.
EPP has greater morbidity than pleurectomy. The major complication rate ranges from 20% to 40% and arrhythmia requiring medical management is the most common complication. The rate of bronchopleural fistula is greater with right sided EPP (3%–20%). In the 1970s, the mortality rate was 31% but as a result of the improvements in techniques and experience it is reported to be as low as 3.8% now.55,56 Mortality is generally due to myocardial infarction and pulmonary emboli.
Local control is better after EPP than P/D.57 The most common problem after pleurectomy is local progression, while after EPP it is systemic failure.48,57 Neither of these procedures provides survival advantage on their own.29
The success of radiotherapy (RT) in the treatment of MPM is limited by the large volume of the tumor and the radiosensitivity of the adjacent vital structures (heart, lung, spinal cord, and esophagus). These factors limit the effective radiation doses that can be given to the patient.
Mesothelial tumor cell seeding along the instrument tracts is common after any pleural intervention and occurs in 15% to 20% of cases (range, 2%–51%).58,59 Boutin et al. randomized 40 MPM patients to either RT or no treatment after any invasive diagnostic procedure. RT consisted of 21 Gy delivered in three fractions using electrons to the site of intervention. No patient in the RT group developed skin nodules while eight of the 20 patients who did not received RT developed metastatic nodules (p < 0.001).58 Another study assigned 28 MPM patients to receive a single 10 Gy dose to the procedure site using electrons. The results were compared with the control group of 30 MPM patients who did not receive RT. There was no difference in tract metastasis formation between the groups (p = 0.53).60 O' Rourke et al. randomized MPM patients to either immediate drain site RT (31 patients) or best supportive care (30 patients). RT was 21 Gy delivered in three fractions. Tract metastases at drain sites were identified in four RT patients compared to three patients who received supportive care (p = 0.75).61 Due to the discrepancies in the findings it is difficult to give a definitive conclusion about prophylactic RT. It should be noted that in these studies the number of patients are small, RT doses and techniques are different and the histology of the tumors was not reported in most cases.62
It is known that RT is effective in the palliation of symptoms of MPM such as dyspnea, pain, superior vena cava syndrome, Pancoast syndrome, and neurologic deficits secondary to brain metastases.63 It was reported that doses above 40 Gy are effective to decrease the pain.64
Gupta et al. retrospectively reviewed 123 MPM patients treated with P/D and adjuvant RT. Median survival was 13.5 months and the one-year local control rate was 46%. In this study two patients died from Grade 5 toxicity within one month of treatment. It was concluded that more extensive surgery followed by external RT might be required to improve local control and overall survival.65
In a phase II study by Rusch et al. EPP followed by hemithoracic RT (median dose 54 Gy) resulted in a median survival of 17 months and a three-year survival rate of 27%. Local recurrence decreased significantly and the most common relapse pattern was distant metastases. All of the patients tolerated the treatment well.66
CHT provides symptom palliation and increase in quality of life and survival. Single agent CHT has response rates of less than 20%, and compared with the best supportive care it does not have a survival advantage. The response rates are improved with combination CHT regimens but the survival data is diverse.67
There are studies on the role of anthracyclines in the treatment of MPM. Anthracyclines are not effective on their own and their combination with platinum derivatives or cyclophosphamides did not give superior results.67–70
A nucleoside analogue, gemcitabine, has limited effect when used as a single agent in MPM but it is more effective when used as a part of a combined CHT regimen. A phase II study by Byrne et al. showed an objective response rate of 47% and one year survival rate of 41%.71 Similar studies showed response rates of 26–33%.72–74
In a phase II study by Favaretto et al. the combination of gemcitabine and carboplatin was reported to be an appropriate option in the treatment of MPM due to its tolerable toxicity and the good response rate. Patients had good clinical benefits and the median survival was 66 weeks.75
Vinorelbine is a vinca alkaloid agent. It has been evaluated in 29 MPM patients with a weekly dose of 30 mg/m2. The response rate was 24% and improvement in general physical symptoms was reported in 41% of patients. It may be a possible treatment for patients who are unable to tolerate combination CHT with a platinum based regimen.76
Pemetrexed is a multi-targeted antifolate drug that inhibits multiple enzymes in the folate metabolism pathway. It enters the cell via the reduced folate carrier and undergoes polyglutamation. Pemetrexed is a potent inhibitor of thymidylate synthase, which is required for DNA synthesis.
A large randomized phase III trial of pemetrexed–cisplatin versus single-agent cisplatin has been reported. A total of 456 chemo-naive MPM patients were randomized. The results showed that the pemetrexed-cisplatin combination was more effective than the cisplatin treatment in terms of median survival (12.1 months vs. 9.3 months, p = 0.020), median time to progressive disease (5.7 months vs. 3.9 months, p = 0.001), and response rate (41% vs. 17%, p = 0.0001). Addition of folic acid and vitamin B12 to 117 patients in the pemetrexed-cisplatin group decreased the toxicities significantly.21,37
Raltitrexed, a thymidylate synthase inhibitor, has been studied in a phase III trial by the EORTC. The combination of raltitrexed-cisplatin was compared with cisplatin alone and the combination group showed an increase in survival (40% vs. 46%, p = 0.048). This study concluded that combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM without harmful effect on their health related to quality of life.38
The most favorable results have been reported with EPP in combination with CHT and postoperative RT, called trimodal therapy. Patients who are candidates for this should be evaluated initially by chest CT, MRI, pulmonary function tests and echocardiography. Patients were considered appropriate for trimodal therapy if they had a Karnofsky performance status of greater than 70%, normal renal and liver function tests, and tumor judged to be completely resectable on the basis of CT, MRI, and echocardiography. Patients should have room air arterial PCO2 less than 45 mm Hg, room air arterial PO2 greater than 65 mm Hg, echocardiography demonstrating an ejection fraction of more than 45%, and a predicted postoperative forced expiratory volume in 1 second (FEV1) of greater than 1 L.
Surgery plus CHT plus hemithoracic RT
In a study by Baldini et al. EPP was followed by four cycles of CHT and hemithoracic RT. Fifty-four percent of patients developed recurrent MPM. The recurrence pattern was local in 35%, abdominal in 26%, contralateral thorax in 17% and distant metastasis in 8%. Time to relapse was longer in the group that received the trimodal therapy. With this approach median survival was 22 months and the three-year survival rate was 34%.77
Sugarbaker et al. reported the result of patients treated with multimodal therapy between 1980 and 1997. EPP was performed on 183 patients, followed by cyclophosphamide-doxorubicin-cisplatin combination chemotherapy (CAP) or carboplatin and paclitaxel, and subsequent hemithoracic RT of median 30.6 Gy. Two- and five-year survival rates were 38% and 15% respectively. However a third of patients had ipsilateral hemithoracic and a third of patients had abdominal relapse. It was concluded that patients with epithelial histology, margin-negative and extrapleural node-negative resection had better survival.55
Yajnik et al. showed that hemithoracic RT was well tolerated after EPP. The most common toxicities according to the Radiation Therapy Oncology Group (RTOG) criteria were grade I or II nausea and vomiting, as well as lung, esophageal and skin toxicities. Only one patient had grade III esophageal toxicity.78
Another study performed in Turkey evaluated EPP followed by RT and CHT. Three-dimensional conformal hemithoracic radiotherapy was delivered to the hemithorax at a median dose of 50.4 Gy in 14 patients. After RT patients received 4 cycles of pemetrexed and cisplatin. The treatment was generally well tolerated. After a median follow up of 16 months, local control was 100%. Six (43%) patients developed abdominal relapse and one (7%) developed distant metastasis.79
CHT plus surgery plus hemithoracic RT
Weder et al. performed a pilot study to evaluate three cycles of neoadjuvant CHT with cisplatin and gemcitabine followed by EPP with or without RT in patients with potentially resectable MPM. Nineteen patients were included, 16 had EPP and 13 of them received postoperative RT. The response rate to neoadjuvant CHT was 32%. The median survival time was 23 months. The treatment was well tolerated.80
A multicenter trial evaluated neoadjuvant CHT followed by EPP and RT. The study included 61 patients with MPM. CHT was three cycles of gemcitabine and cisplatin delivered to 58 patients. EPP was performed on 45 patients (74%) and in 37 patients (61%) resection was complete. Postoperative RT was delivered to 36 patients. The median survival was 19.8 months for all patients and 23 months for those who underwent EPP.81
Flores et al. delivered four cycles of gemcitabine and cisplatin to 19 MPM patients. Patients without disease progression underwent EPP (nine patients). Eight of them received hemithoracic RT of 54 Gy. Median survival for all patients was 19 months. Patients who had EPP had a median survival of 33.5 months. Patients with unresectable tumors had median survival of nine months.82
New therapeutic approaches
Intensity modulated RT
It is known that hemithoracic RT improves local control after EPP. Intensity modulated RT (IMRT) provides better dose distribution of the target volume and protects the normal structures surrounding the target. Rice et al. reported benefits of local control with IMRT, however, most patients died due to distant metastases.83 Although IMRT is effective for targeting well, the dose to the contralateral lung is high. Allen et al. reported that IMRT treatment for mesothelioma after EPP and adjuvant CHT resulted in a high rate of fatal pneumonitis when standard dose parameters were used. V5 (volume of lung receiving 5 Gy or more) and mean lung dose should be considered in addition to V20 (volume of lung receiving 20 Gy or more) to determine tolerance levels in patients.84
Intracavitary therapy is the instillation of chemotherapeutic or immunotherapeutic compounds directly to the pleural space. Mesothelioma patients with greater amounts of intratumoral lymphocytic infiltration had improved median survival rates. Several groups have studied intrapleural immunotherapy using granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-2 and γ-interferon.85–90 The studies with γ-interferon showed a response rate of 45% in early-stage disease.86,87
Gene therapy is based on the idea of infecting malignant cells via viral gene systems, making them vulnerable to antiviral agents. Recombinant adenovirus, genetically engineered to contain the herpes simplex virus thymidine kinase gene, is most commonly used for this purpose. In vitro and clinical studies showed tumoral regression after the administration of ganciclovir.91,92
Advances have been made in the diagnosis and treatment of MPM over the last decade. Accurate diagnosis and prognosis of the disease is now more likely, however, it is still not possible to achieve long term survival. Based on the fact that none of the treatment types are effective on their own, patients with good performance status should undergo multimodal treatments. Improvement in local control with multimodal approaches resulted in more distant metastases, more effective systemic treatments should be sought. Novel therapeutic options such as immunotherapy, angiogenesis inhibitors and vaccines need further investigation.
Special thanks to Dr. Fadıl Akyol (Professor of Radiation Oncology, Hacettepe University Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey) and Dr. Salih Emri (Associate Professor of Medicine, Hacettepe University Faculty of Medicine, Department of Chest Diseases, Ankara, Turkey) for their work and support for the treatment of malignant pleural mesothelioma.